Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

Neuropharmacology. 2019 Apr:148:50-67. doi: 10.1016/j.neuropharm.2018.12.018. Epub 2018 Dec 17.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5- (5M) and 10- (10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid β1-42 (sAβ1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3β (GSK-3β), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAβ1-42 level, decreased IR expression and increased GSK-3β activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.

Keywords: Alzheimer disease; Cognition; Galactose; Metabolism; Positron-emission tomography; Transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / chemically induced
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / psychology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism
  • Cognitive Dysfunction / chemically induced
  • Cognitive Dysfunction / prevention & control*
  • Cognitive Dysfunction / psychology*
  • Fluorodeoxyglucose F18 / metabolism
  • Functional Neuroimaging
  • Galactose / administration & dosage
  • Galactose / pharmacology*
  • Glucagon-Like Peptide 1 / blood
  • Glucose Tolerance Test
  • Glycogen Synthase Kinase 3 beta / biosynthesis
  • Hippocampus / metabolism
  • Insulin / blood
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / metabolism
  • Positron-Emission Tomography
  • Rats
  • Receptor, Insulin / biosynthesis
  • Streptozocin

Substances

  • Amyloid beta-Peptides
  • Insulin
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Fluorodeoxyglucose F18
  • Streptozocin
  • Glucagon-Like Peptide 1
  • Receptor, Insulin
  • Glycogen Synthase Kinase 3 beta
  • Galactose